DESCRIPTION (Applicant's Description) The overall objective of this program project is to continue the study and improvement of high dose conformal radiation therapy treatments for cancer. The previous program project studied plan optimization, conformal dose delivery techniques, patient related geometrical uncertainties, and helped define the dose/volume tolerance boundaries of treatment limiting normal tissues while showing that conformal therapy allowed significantly higher tumor doses to be delivered without increasing complications. Currently, increasingly sophisticated tools (automated optimization software, intensity modulated radiation therapy (IMRT), improved methods for patient and target volume localization and models to begin to more fully characterize the response of tissues to irradiation) are available to leverage the progress of the previous grant toward further optimization of individual patient treatments. Thus, this program project will work to optimize the entire treatment planning and delivery process. Project 1 will examine and evaluate enhanced automated optimization capabilities which begin to include all relevant parts of the planning/delivery process. Project 2 will investigate and evaluate the dosimetric impact and limitations of different optimization strategies and IMRT delivery capabilities. Project 3 will research and evaluate the benefits of inclusion of patient-related geometric uncertainties into the calculation, compilation and treatment of conformal dose distributions. Project 4 will treat patients to unprecedented high dose levels as it completes normal tissue tolerance dose escalation trials in the brain, liver, and lung, finishes normal tissue dose reduction studies in the head/neck and prostate, and moves on to Phase II (lung, liver, brain) and head/neck and prostate escalation trials. The projects are supported by Core A (administrative and statistical support), Core B (automated treatment delivery process), Core C (quality assurance for an optimized treatment planning/delivery process), and Core D (computer software support). The investigators possess a unique combination of capabilities to successfully perform this work, based on more than 14 years experience in clinical 3-D treatment planning, conformal therapy, dose escalation, and computer-controlled treatment delivery.